Dr. Prisciandaro is a postdoctoral fellow in the Clinical Neuroscience Division (CND) of the Department of Psychiatry at the Medical University of South Carolina (MUSC); he will join the faculty as an Assistant Professor upon completion of his fellowship in July, 2012. Dr. Prisciandaro seeks a Mentored Patient-Oriented Research Career Development Award (K23), through the National Institutes of Health-National Institute on Alcohol Abuse and Alcoholism (NIH/NIAAA), to facilitate his career as an independent investigator conducting patient-oriented research in individuals with co-occurring alcohol use and bipolar disorders. Candidate: Dr. Prisciandaro is a clinical psychologist with extensive training in substance use and mood disorders research and practice, quantitative methods, and initial training in functional Magnetic Resonance Imaging (fMRI). His long-term career goal is to become an independent clinical scientist in the area of patient- oriented substance use and mood disorders research, with an emphasis on using neuroimaging to develop and test mechanistic models of co-occurring alcohol use and bipolar disorders. In order to realize this goal, Dr. Prisciandaro requires additional training. During the proposed award, Dr. Prisciandaro will 1) obtain sophisticated knowledge of the neurobiology of alcohol use and bipolar disorders, 2) learn how to design, conduct, and analyze fMRI and proton Magnetic Resonance Spectroscopy (1H-MRS) experiments to investigate the neurobiology of alcohol use and bipolar disorders, 3) augment existing clinical research skills, and 4) improve grantsmanship in order to successfully compete for an Independent Research Award (R01). Environment: MUSC ranks among the top 10 medical schools in the country for addiction education, and the MUSC College of Medicine has 7 departments ranked in the top 25 nationally in NIH funding including the Department of Psychiatry. Addictions collaborations span several departments and include 4 NIH center and 2 T32 addiction-research training grants. Across departments, over 30 faculty are engaged in addiction research; a number of these faculty will be mentors. Dr. Prisciandaro's proposed mentors/collaborators are international and national experts, including Drs. Raymond Anton, Jane Joseph, Truman Brown, Kathleen Brady, Mary Phillips (offsite), Alan Swann (offsite), Peter Kalivas, Hugh Myrick, and Bryan Tolliver. Study procedures will take place through the Clinical Neuroscience Division (CND). The CND (Dr. Brady-Director) will provide the infrastructure for the execution of the proposed research. Neuroimaging will be conducted at MUSC's Center for Advanced Imaging Research (CAIR; Dr. Brown-Director). CAIR's Siemens 3T Trio MRI, with integrated fMRI paradigm equipment, operates with a 100% mandate for research and is accompanied by comprehensive informatics support. Seminars, pilot project programs, and research services are further available through MUSC's Center for Drug and Alcohol Programs, Department of Neurosciences, South Carolina Clinical and Translational Research Institute, and Division of Biostatistics and Epidemiology. Research: Bipolar disorder (BD) is the Axis I psychiatric condition most strongly associated with substance use disorders (SUD); co-occurring BD and SUD are associated with devastating clinical outcomes. Research suggests that dysregulated glutamate transmission may be partially responsible for co-occurring SUD and BD, both directly and through its impact on neurobehavioral deficits that are common to both SUD and BD. Though promising, this hypothesis is based on indirect evidence, as there have been virtually no neuroimaging studies involving individuals with co-occurring BD and SUD. The proposed study will provide a first evaluation of anterior cingulate (ACC) glutamate, impulsivity (response inhibition), and reward sensitivity (sensitivity to alcohol cues) as contributors to comorbidity between BD and alcohol dependence (AD) using 1H-MRS and fMRI in individuals with co-occurring AD and euthymic BD, individuals with euthymic BD alone, individuals with AD alone, and a matched control group. In Aim 1, we predict that individuals with co-occurring AD and BD will have significantly different ACC glutamate (by 1H-MRS) relative to individuals with AD or BD alone.InAim 2, we predict that individuals with co-occurring AD and BD will demonstrate significantly less ACC/frontal (e.g., right inferior frontal cortex) bran activity (by fMRI Bold response) when asked to inhibit a prepotent response relative to individuals with AD or BD alone. In Aim 3, we predict that individuals with co- occurring AD and BD will have significantly greater ventral striatal and ACC/frontal activity (by fMRI) when exposed to alcohol cues relative to individuals with AD or BD alone. Control subjects are expected to have the most normal levels of ACC glutamate, highest levels of ACC/frontal activity to response inhibition, and lowest levels of striatal and frontal activity to alcohol cues Comparisons between AD and BD will be exploratory given that these groups have never been compared. The relationship between ACC glutamate (by 1H-MRS), neural activation to alcohol cues (fMRI) and response inhibition (fMRI), and AD/BD diagnosis will be explored. The proposed study will provide evidence for or against glutamate neurotransmission as a key brain system underlying co-occurring AD and BD, and will provide a paradigm for examining the mechanistic effects of glutamatergic drugs for the treatment of AD, BD, and AD+BD. PUBLIC HEALTH RELEVANCE: Bipolar Disorders (BD) and substance use disorders (SUD) co-occur very frequently, and co-occurring BD and SUD are associated with devastating public health costs. Unfortunately, there has been very little neurobiological research involving individuals with co-occurring BD and SUD to guide the development of effective treatments for this treatment-resistant population. In response to this clinical need, the proposed study will evaluate a potential mechanistic model of BD and alcohol dependence (AD) co-occurrence, involving shared neurochemical and neurobehavioral dysregulations, that could help to identify novel therapeutic targets for individuals with co-occurring BD and AD.